Identification of exhausted CD8+ T cells in low tumor mutation burden breast cancer patients

Abstract

Abstract Tumor immunogenicity is generally thought to be correlated with increased tumor mutation burden and the resulting neoantigen driven T cell reactivity to cancer cells. This immunogenicity results in the formation of tumor specific, but exhausted tumor infiltrating CD8+ T cells (TILex). Breast cancer tumors, which are predominantly low mutation burden, are widely viewed as non-immunogenic. Here we demonstrate that subsets of both triple negative and estrogen receptor positive breast cancer patients have primary tumors heavily infiltrated by tumor specific CD8+ TILex. CD8+ TILex in breast cancer patients were demonstrated to coexpress PD-1 and CD39 and showed a significant reduction of IFNγ, TNFα, and IL-2 production capacity. Like melanoma and colorectal CD8+ TILex, CD8+ TILex human breast tumors had increased expression of CD103, CD38, and TIM-3 in addition to loss of KLRG1 and CD127 expression. Similarly, melanoma, colorectal, and breast tumor CD8+ TILex shared transcriptional signatures identified by single cell sequencing. T cell receptor sequencing revealed a distinct repertoire of CD8+ TILex as compared to other CD8+ TILs from the same tumors, suggesting them to be a unique population in response to tumor antigen. Finally, we demonstrated that increased levels of CD8+ TILex in human breast tumors are not associated with higher levels of tumor mutation burden, as assessed by a tumor mutation load oncogene panel. This work suggests that a subset of breast cancer patients have inflamed, tumors associated with the presence of exhausted CD8+ T cells and that these patients may benefit from immunotherapeutic interventions.